PROJECT SUMMARY Common to virtually all neurodegenerative diseases and brain disorders are changes in a glial cell type called an astrocyte, which become ?reactive?. Astrocytes ordinarily provide critical support for neurons and only turn into reactive astrocytes (RAs) following injury or development of disease. A longstanding issue which has remained unknown is whether RAs contribute to, or help alleviate, disease progres- sion. Our long-term goal is to increase understanding of the molecular and cellular underpinnings of diseases and disorders of the nervous system through increased understanding of the role of reactive astrocytes. The objective of this proposal is to deliver a new strategy to selectively alter (eliminate, in- crease, or decrease) the function of only RAs at any point in the progression of nervous system disor- ders. One such disorder for which new treatments are needed is epilepsy. Despite being the third most common neurological disorder in the U.S. after Alzheimer?s disease and stroke, epilepsy is among the least understood of the major chronic medical conditions. Two aims are proposed, with the goal of characterizing this new strategy and providing proof-of-principle for using the approach for the selective manipulation of RAs in disease: In Aim 1, we will first characterize a novel reactive astrocyte inducible Cre transgenic strategy to selectively manipulate RAs in brain disease. In Aim 2, we will then use the new approach to either selectively eliminate RAs or reprogram them back into non-reactive astrocytes at various stages during the development of epilepsy. Our work will provide new knowledge on the pro- tective vs. detrimental roles of reactive astrocytes in the development of epilepsy. The rationale for the proposed research is that new insight into the role of reactive cell types in disease is an important goal for the development of more efficacious treatments. We anticipate that this research will be transforma- tive, as we will introduce to the research community a powerful new strategy to investigate the role of reactive astrocytes in any disease or disorder of the nervous system.